The objectives of this proposed research are to make creative contributions to the total synthesis of naturally occurring substances possessing clinically significant biological activity. This grant will continue to address the development of new stereoselective reactions and the application of this methodology to the asymmetric synthesis of polyketide-derived antibiotics and anti-neoplastic agents. The synthesis targets will include aflastatin A, amphidinol 3, pectenotoxin, callipeltoside A, cochleamycin, and hexacyclinic acid. Enantioselective processes developed within this research program have been integrated into the proposed synthesis plans for the indicated target structures. The methodological studies dealing with reaction discovery will emphasize the development of reactions for controlling and ultimately predicting the stereochemical course of complex aldol processes. The ongoing goal of these studies has been to reveal some of the general rules for predicting the stereochemical outcome of complex aldol fragment coupling reactions. Along with polynucleotides, peptides and polysaccharides, polyketides represent the fourth broad family of naturally occurring materials that are assembled from common subunits. In extending the family of naturally occurring materials that are assembled through complex aldol addition reactions is a far greater challenge than the amide construction analogy. Our long-term objective has been the development all of the necessary tools for the efficient assemblage of complex polypropionate and polyacetate targets. Asymmetric catalysis has been directed to the construction of chiral building blocks. Chiral enolate methodology has been developed for stereoregulated aldol processes, and studies on double stereodifferentiating aldol reactions have revealed how to improve the design predictability of these fragment coupling reactions. Our goal has been to set in place all of the reactions necessary for the rapid assemblage of any polyketide target structure.